Background
Cerebral infarction induces substantial neuronal apoptosis and neuroinflammation in the ipsilateral nonischemic thalamus and hippocampus, with a critical correlation to post-stroke cognitive impairment. Poly (ADP-ribose) polymerase 9 (PARP9) has been implicated in apoptosis and inflammation across various diseases, while its role in remote brain damage after cerebral infarction remains unclear. This study aims to investigate the role of PARP9 in mediating neuronal apoptosis and neuroinflammation in remote brain regions after distal middle cerebral artery occlusion (dMCAO) and explore its contribution to secondary brain damage and cognitive decline.
Conclusions
Our findings demonstrate that PARP9 aggravates neural damage and cognitive decline after cerebral infarction by promoting neuronal apoptosis and neuroinflammation, partly via the PI3K pathway.
Methods
Seventy-four hypertensive rats were randomly assigned to either the sham-operated group or the dMCAO group. The dMCAO group was further subdivided into PARP9 knockdown and overexpression subgroups, with their respective control groups, modulated by adeno-associated viruses (AAV) carrying siScramble, siPARP9, Scramble, or PARP9. Within the PARP9 knockdown subgroup, rats were further treated with either a phosphoinositide 3-kinase (PI3K) inhibitor,2-(4-morpholinyl)-8-phenyl-chromone (LY294002), or vehicle. Spatial learning and memory deficits were evaluated using the Morris water maze test. Secondary neuronal apoptosis and neuroinflammation were quantified 7 days post-dMCAO using Nissl staining, immunofluorescence, immunohistochemistry, TUNEL, and Western blot analysis.
Results
PARP9 expression was significantly upregulated in the ipsilateral thalamus and hippocampus after dMCAO, correlating with neuronal apoptosis and neuroinflammation. PARP9 was localized in both neurons and microglia. PARP9 knockdown reduced neuronal apoptosis, neuroinflammation, and microglial activation in the ipsilateral thalamus and hippocampus, and meanwhile improved the cognitive function. In contrast, PARP9 overexpression exacerbated these outcomes. Mechanistically, PARP9 knockdown activated the PI3K pathway, and inhibition of this pathway with LY294002 partially reversed the effects, reinstating neuronal apoptosis, neuroinflammation, and cognitive deficits. Conclusions: Our findings demonstrate that PARP9 aggravates neural damage and cognitive decline after cerebral infarction by promoting neuronal apoptosis and neuroinflammation, partly via the PI3K pathway.